The long-term effects of pre-treatment with activated protein C in a rat model of compression-induced spinal cord injury

Taoka, Yuji; Schlag, Michael; Hopf, R.; Redl, Heinz

doi:10.1038/sj.sc.3101096

Cited by 14 publications

(9 citation statements)

References 36 publications

(34 reference statements)

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“…APC also protects against diabetic endothelial and glomerular injury [12], and is also protective in animal models of sepsis, ischemia-reperfusion injury of kidney and lung, and thrombosis models [13]. Regarding central nervous system disorders, APC is protective in rodent models of spinal cord injury [14], amyotrophic lateral sclerosis[15], and multiple sclerosis [16]. …”

Section: Introductionmentioning

confidence: 99%

Preclinical Safety and Pharmacokinetic Profile of 3K3A-APC, a Novel, Modified Activated Protein C for Ischemic Stroke

Williams¹,

Zloković

Griffin

et al. 2012

Current Pharmaceutical Design

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Activated protein C (APC), a protease with anticoagulant and cytoprotective activities, protects neurons and cerebrovascular endothelium from ischemic injury. A recombinant APC, drotrecogin alfa (activated) (DrotAA) (Xigris®), was approved by the Food and Drug Administration for the treatment of sepsis; however, serious bleeding was a dose-limiting side effect. A modified APC, containing 405 amino acid residues, 3K3A-APC, was designed to possess significantly reduced anticoagulant activity (< 10 %) while maintaining full cytoprotective properties. The preclinical safety assessment of 3K3A-APC was conducted to support initiation of ischemic stroke clinical trials. The safety and toxicokinetics of 3K3A-APC were studied in CD-1 mice and cynomolgus monkeys. Multiple-dose (14-day), intravenous GLP toxicology assessed toxicity, histopathology, immunogenicity, and toxicokinetics. Dose-related increases in plasma total 3K3A-APC were observed in mice and monkeys with no evidence of accumulation over 14 days. The elimination T1/2 in monkeys was 1 hour. 3K3A-APC was well tolerated in mice and monkeys, and no signs of 3K3A-APC toxicity were identified in mice or monkeys at any time. Additionally, wild-type APC (DrotAA) was studied to obtain comparative anticoagulant data using clotting assays. Anticoagulant activity of 3K3A-APC was observed in monkeys at doses of 1 and 5 mg/kg/day. In contrast, DrotAA showed prolongation of clotting assays in monkeys at doses 1/10th of those showing effects with 3K3A-APC. Based upon the anticoagulant profiles, the risk for APC-induced bleeding in clinical trials of 3K3A-APC is greatly reduced relative to wild type APC which makes this new drug a feasible therapy for ischemic stroke patients.

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Section: Introductionmentioning

confidence: 99%

Preclinical Safety and Pharmacokinetic Profile of 3K3A-APC, a Novel, Modified Activated Protein C for Ischemic Stroke

Williams¹,

Zloković

Griffin

et al. 2012

Current Pharmaceutical Design

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show abstract

“…APC also protects against diabetic endothelial and glomerular injury12 and in animal models of sepsis, ischemia–reperfusion injury of kidney and lung, and thrombosis models 13. Regarding central nervous system disorders, APC is protective in rodent models of spinal cord injury,14 amyotrophic lateral sclerosis,15 and multiple sclerosis 16…”

mentioning

confidence: 99%

Differential Neuroprotection and Risk for Bleeding From Activated Protein C With Varying Degrees of Anticoagulant Activity

Wang

Thiyagarajan

Chow

et al. 2009

Stroke

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Background and Purpose-Activated protein C (APC), a protease with anticoagulant and cytoprotective activities, protects neurons and endothelium from ischemic injury. Drotrecogin-alfa activated, a hyperanticoagulant form of human recombinant APC, is currently being studied in patients with ischemic stroke. How changes in APC anticoagulant activity influence APC's neuroprotection and risk for bleeding is not clear. Methods-We used neuronal and brain endothelial cell injury models and middle cerebral artery occlusion in mice to compare efficacy and safety of drotrecogin-alfa activated and human 3K3A-APC, an APC nonanticoagulant mutant. Results-Drotrecogin-alfa activated and 3K3A-APC exhibited 148% and 10% of plasma-derived APC's anticoagulant activity and differ in the carbohydrate content. 3K3A-APC protected mouse neurons from N-methyl-D-aspartate-induced apoptosis and human brain endothelial cell from oxygen-glucose deprivation with 1.8-and 3.1-fold greater efficacy than drotrecogin-alfa activated. Given 5 minutes before transient middle cerebral artery occlusion, 3K3A-APC and drotrecogin-alfa activated (0.5 and 2 mg/kg intravenously) reduced comparably and dose-dependently the infarction lesion up to 85%. 3K3A-APC, but not drotrecogin-alfa activated, improved neurological score dose-dependently (PϽ0.05). 3K3A-APC did not cause bleeding. In contrast, drotrecogin-alfa activated dose-dependently increased hemoglobin content in postischemic brain. After permanent middle cerebral artery occlusion, 3K3A-APC multidose therapy (1 mg/kg intravenously at 12 hours and 1, 3, 5, and 7 days) improved functional recovery and reduced infarction by 60% with no risk for bleeding, whereas drotrecogin-alfa activated increased hemoglobin deposition in the postischemic brain and showed relatively modest neuroprotection. Conclusions-Nonanticoagulant

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“…2003; Zlokovic et al. 2005), spinal cord injury (Taoka et al. 2000) and multiple sclerosis (Han et al.…”

mentioning

confidence: 99%

Species‐dependent neuroprotection by activated protein C mutants with reduced anticoagulant activity

Guo

Wang

Singh

et al. 2009

Journal of Neurochemistry

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Activated protein C (APC) is a protease with anticoagulant and cytoprotective activities. APC is neuroprotective in rodent models of stroke. But, an APC variant with reduced anticoagulant activity, 3K3A-APC, compared to wild-type APC shows greater neuroprotection with no risk for bleeding in stroke models. To determine whether 3K3A-APC exhibits species-dependent neuroprotection similar to that as seen with wild-type APC, we studied murine and human recombinant 3K3A-APC mutants which show approximately 80% reduced anticoagulant activity. Murine 3K3A-APC (0.2 mg/kg i.v.) administered at 4 h after embolic stroke improved substantially functional outcome and reduced by 80% the infract volume 7 days after stroke. Human 3K3A-APC was neuroprotective after embolic stroke in mice, but at significantly higher concentrations (i.e. 2 mg/kg i.v.). Speciesdependent neuroprotection, i.e. murine > human 3K3A-APC, was confirmed in a mouse model of permanent middle cerebral artery occlusion. Human 3K3A-APC had by fivefold greater cytoprotective activity than murine 3K3A-APC in oxygen-glucose deprivation model in human brain endothelial cells, whereas murine 3K3A-APC was by 2.5-fold more potent than human 3K3A-APC in a mouse model of NMDA-induced neuronal apoptosis. Thus, 3K3A-APC exhibits speciesdependent neuroprotection which should be taken into account when designing human trials for ischemic stroke with APC mutants.

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The long-term effects of pre-treatment with activated protein C in a rat model of compression-induced spinal cord injury

Cited by 14 publications

References 36 publications

Preclinical Safety and Pharmacokinetic Profile of 3K3A-APC, a Novel, Modified Activated Protein C for Ischemic Stroke

Preclinical Safety and Pharmacokinetic Profile of 3K3A-APC, a Novel, Modified Activated Protein C for Ischemic Stroke

Differential Neuroprotection and Risk for Bleeding From Activated Protein C With Varying Degrees of Anticoagulant Activity

Species‐dependent neuroprotection by activated protein C mutants with reduced anticoagulant activity

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